US10450378B2ActiveUtilityPatentIndex 71
Cytotoxic and anti-mitotic compounds, and methods of using the same
Est. expirySep 17, 2034(~8.2 yrs left)· nominal 20-yr term from priority
Inventors:WINTERS GEOFFREY CRICH JAMES RGARNETT GRAHAM ALBERT EDWINMANDEL ALEXANDER LAURENCEHSIEH TOM HAN HSIAOBOURQUE ELYSE MARIE JOSEEBARNSCHER STUART DANIEL
A61P 35/00H10W 90/00C07K 2317/73A61K 47/54C07K 16/2878A61K 47/6855C07K 16/30C07K 2317/24C07K 16/2887C07K 16/32C07K 5/0205A61K 38/06A61K 38/00A61K 47/6867A61K 47/6813A61K 47/6851C07D 207/448C07D 207/08A61K 38/05C07K 7/02A61K 47/68H10K 59/131H10K 59/1201H10K 71/00H10K 77/111H10K 59/18A61K 39/395
71
PatentIndex Score
2
Cited by
207
References
61
Claims
Abstract
Compounds having cytotoxic and/or anti-mitotic activity are disclosed. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed. Also disclosed are compositions having the structure: (T)-(L)-(D), wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound having cytotoxic and/or anti-mitotic activity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from: amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, amino-heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from aryl, aryl-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, carboxyl, carboxamide, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl, guanidino, halo, C 1 -C 6 haloalkyl, heterocyclyl, heterocyclyl-C 1 -C 6 alkyl, hydroxyl, and thio; or
R 1 is R a R b NCH(R c )—;
R a is selected from: H and C 1 -C 6 alkyl;
R b is C 1 -C 6 alkyl; and
R c is R d —C(CH 3 ) 2 —; and
R d is selected from: H, aryl, C 3 -C 7 cycloalkyl, and heteroaryl, each of which is optionally substituted with one or more substituents selected from: C 1 -C 4 acylthio, C 2 -C 4 alkenyl, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 alkyloxy, amino, amino-C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-C 1 -C 4 alkyl, and thio, wherein C 2 -C 4 alkenyl, C 1 -C 4 alkylamino and C 1 -C 4 alkyloxy are further optionally substituted with one substituent selected from C 1 -C 4 alkylaryl, hydroxyl, and thio; or
R b and R c taken together with the atoms to which they are each bonded form a heterocyclyldiyl;
R 2 is aryl or aryl-C 1 -C 6 alkyl each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl; and
X is —C(O)NHCH(CH 2 R 3 )—; and
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl.
2. The compound according to claim 1 , wherein R 1 is selected from: amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, amino-heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halo.
3. The compound according to claim 1 , wherein R 1 is R a R b NCH(R c )—.
4. The compound according to claim 1 having Formula Ie:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is aryl or aryl-C 1 -C 6 alkyl, each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl;
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl; and
R 4 and R 5 are each independently selected from: H and C 1 -C 6 alkyl.
5. The compound according to claim 4 , wherein R 4 and R 5 are each C 1 -C 6 alkyl.
6. The compound according to claim 4 , wherein R 4 is H, and R 5 is C 1 -C 6 alkyl.
7. The compound according to claim 1 having Formula Ih:
or Formula Ik:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is aryl or aryl-C 1 -C 6 alkyl, each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl; and
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl.
8. The compound according to claim 7 , wherein R 3 is aryl optionally substituted with one substituent selected from amino and hydroxyl.
9. The compound according to claim 1 selected from the following, or a pharmaceutically acceptable salt thereof:
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-((S)-1-(4- aminophenylsulfonamido)-1-oxo-3- phenylpropan-2-ylamino)-1- methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 11); and
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-((S)-1-(4- aminophenylmethylsulfonamido)-1- oxo-3-phenylpropan-2-ylamino)-1- methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 14).
10. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
11. A method of inhibiting cancer in a mammal, relieving cancer in a mammal, or relieving the symptoms of cancer in a mammal comprising administering to a mammal in need thereof an effective amount of the compound according to claim 1 .
12. A method of inhibiting tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of the compound according to claim 1 .
13. A composition of Formula II:
(T)-(L)-(D) II
wherein (T) is a targeting moiety, (L) is a linker, and (D) is the compound according to claim 1 .
14. The composition according to claim 13 , wherein R 1 is selected from: amino-C 1 -C 6 alkyl, amino-aryl, amino-C 3 -C 7 cycloalkyl, amino-heterocyclyl, and heterocyclyl, each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halo.
15. The composition according to claim 13 , wherein R 1 is R a R b NCH(R c )—.
16. The composition according to claim 13 , wherein (D) is a compound having Formula Ie:
wherein:
R 2 is aryl or aryl-C 1 -C 6 alkyl, each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl;
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl; and
R 4 and R 5 are each independently selected from: H and C 1 -C 6 alkyl.
17. The composition according to claim 16 , wherein R 4 and R 5 are each C 1 -C 6 alkyl.
18. The composition according to claim 16 , wherein R 4 is H, and R 5 is C 1 -C 6 alkyl.
19. The composition according to claim 13 , wherein (D) is a compound having Formula Ih:
or Formula Ik:
wherein:
R 2 is aryl or aryl-C 1 -C 6 alkyl, each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl; and
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl.
20. The composition according to claim 19 , wherein R 3 is aryl optionally substituted with one substituent selected from amino and hydroxyl.
21. The composition according to claim 13 , wherein (D) is a compound selected from the following:
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-((S)-1-(4- aminophenylsulfonamido)-1-oxo-3- phenylpropan-2-ylamino)-1- methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 11); and
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-((S)-1-(4- aminophenylmethylsulfonamido)-1- oxo-3-phenylpropan-2-ylamino)-1- methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 14).
22. The composition according to claim 13 , wherein (L)-(D) has the following structure:
23. The composition according to claim 13 , wherein (T) is a monoclonal antibody or antibody fragment.
24. The composition according to claim 23 , wherein the monoclonal antibody or antibody fragment is a bispecific antibody or antibody fragment.
25. The composition according to claim 23 , wherein the monoclonal antibody or antibody fragment specifically binds to a cancer cell antigen.
26. A pharmaceutical composition comprising the composition according to claim 13 and a pharmaceutically acceptable carrier, diluent or excipient.
27. A method of inhibiting cancer in a mammal, relieving cancer in a mammal, or relieving the symptoms of cancer in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 13 .
28. A method of inhibiting tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 13 .
29. A compound selected from the following, or a pharmaceutically acceptable salt thereof:
(S)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N-((3R,4S,5S)- 3-methoxy-1-((S)-2-((1R,2R)-1- mcthoxy-2-methyl-3-oxo-3-((S)-1- oxo-3-phenyl-1-(4-(2,2,2- trifluoroacetamido)phenyl- sulfonamido)propan-2- ylamino)propyl)pyrrolidin-1-yl)-5- methyl-1-oxoheptan-4-yl)-N,3- dimethylbutanamide (Compound 10); and
(S)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N-((3R,4S,5S)- 3-methoxy-1-((S)-2-((1R,2R)-1- methoxy-2-methyl-3-oxo-3-((S)-1- oxo-3-phenyl-1-(4-(2,2,2- trifluoroacetamido) phenylmethylsulfonamido)propan- 2-ylamino)propyl)pyrrolidin-1-yl)- 5-methyl-1-oxoheptan-4-yl)-N,3- dimethylbutanamide (Compound 13).
30. The composition according to claim 13 , wherein (L)-(D) is formed by reacting (D) with a compound:
HO-AA 1 -AA 2 -NH-Anchor
wherein AA 1 and AA 2 are each independently an amino acid, and Anchor comprises a functional group that forms a covalent bond with (T).
31. The composition according to claim 30 , wherein Anchor further comprises a stretcher.
32. The composition according to claim 13 , wherein (L) does not include a self-immolative group.
33. The composition according to claim 21 , wherein (L)-(D) is formed by reacting (D) with a compound:
HO-AA 1 -AA 2 -NH-Anchor
wherein AA 1 and AA 2 are each independently an amino acid, and Anchor comprises a functional group that forms a covalent bond with (T).
34. The composition according to claim 33 , wherein Anchor further comprises a stretcher.
35. The composition according to claim 21 , wherein (L) does not include a self-immolative group.
36. The composition according to claim 21 , wherein (T) is a monoclonal antibody or antibody fragment.
37. The composition according to claim 36 , wherein the monoclonal antibody or antibody fragment is a bispecific antibody or antibody fragment.
38. The composition according to claim 36 , wherein the monoclonal antibody or antibody fragment specifically binds to a cancer cell antigen.
39. A pharmaceutical composition comprising the composition according to claim 21 and a pharmaceutically acceptable carrier, diluent or excipient.
40. A method of inhibiting cancer in a mammal, relieving cancer in a mammal, or relieving the symptoms of cancer in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 21 .
41. A method of inhibiting tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 21 .
42. The composition according to claim 22 , wherein (T) is a monoclonal antibody or antibody fragment.
43. The composition according to claim 42 , wherein the monoclonal antibody or antibody fragment is a bispecific antibody or antibody fragment.
44. The composition according to claim 42 , wherein the monoclonal antibody or antibody fragment specifically binds to a cancer cell antigen.
45. A pharmaceutical composition comprising the composition according to claim 22 and a pharmaceutically acceptable carrier, diluent or excipient.
46. A method of inhibiting cancer in a mammal, relieving cancer in a mammal, or relieving the symptoms of cancer in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 22 .
47. A method of inhibiting tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 22 .
48. The compound according to claim 1 having Formula Ib:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is aryl or aryl-C 1 -C 6 alkyl, each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl;
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl; and
R 4 and R 5 are each independently selected from: H and C 1 -C 6 alkyl.
49. The composition according to claim 13 , wherein (D) is a compound having Formula Ib:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is aryl or aryl-C 1 -C 6 alkyl, each substituted with one or more substituents selected from: amino, amino-C 1 -C 6 alkyl and amino-C 3 -C 7 cycloalkyl;
R 3 is selected from: aryl, heteroaryl, and C 3 -C 7 cycloalkyl, each optionally substituted with one substituent selected from amino and hydroxyl; and
R 4 and R 5 are each independently selected from: H and C 1 -C 6 alkyl.
50. The compound according to claim 1 selected from the following, or a pharmaceutically acceptable salt thereof:
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-(((S)-1-((4- (aminomethyl)phenyl)sulfonamido)- 1-oxo-3-phenylpropan-2-yl)amino)- 1-methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 24);
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-(((S)-1-(((4- (aminomethyl)phenyl)methyl) sulfonamido)-1-oxo-3- phenylpropan-2-yl)amino)-1- methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 28); and
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-((S)-1-(4-(1- aminocyclopropyl)phenylsulfonamido)- 1-oxo-3-phenylpropan-2- ylamino)-1-methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 32).
51. The composition according to claim 13 , wherein (D) is a compound selected from the following:
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-(((S)-1-((4- (aminomethyl)phenyl)sulfonamido)- 1-oxo-3-phenylpropan-2-yl)amino)- 1-methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 24);
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-(((S)-1-(((4- (aminomethyl)phenyl)methyl) sulfonamido)-1-oxo-3- phenylpropan-2-yl)amino)-1- methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 28); and
(S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-((S)-1-(4-(1- aminocyclopropyl)phenylsulfonamido)- 1-oxo-3-phenylpropan-2- ylamino)-1-methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-3- methoxy-5-methyl-1-oxoheptan-4- yl)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3- dimethylbutanamide (Compound 32).
52. The composition according to claim 51 , wherein (L)-(D) is formed by reacting (D) with a compound:
HO-AA 1 -AA 2 -NH-Anchor
wherein AA 1 and AA 2 are each independently an amino acid, and Anchor comprises a functional group that forms a covalent bond with (T).
53. The composition according to claim 52 , wherein Anchor further comprises a stretcher.
54. The composition according to claim 51 , wherein (L) does not include a self-immolative group.
55. The composition according to claim 51 , wherein (T) is a monoclonal antibody or antibody fragment.
56. The composition according to claim 55 , wherein the monoclonal antibody or antibody fragment is a bispecific antibody or antibody fragment.
57. The composition according to claim 55 , wherein the monoclonal antibody or antibody fragment specifically binds to a cancer cell antigen.
58. A pharmaceutical composition comprising the composition according to claim 51 and a pharmaceutically acceptable carrier, diluent or excipient.
59. A method of inhibiting cancer in a mammal, relieving cancer in a mammal, or relieving the symptoms of cancer in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 51 .
60. A method of inhibiting tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of the composition according to claim 51 .
61. A compound selected from the following, or a pharmaceutically acceptable salt thereof:
(S)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N-((3R,4S,5S)- 3-methoxy-1-((S)-2-((1R,2R)-1- methoxy-2-methyl-3-oxo-3-(((S)-1- oxo-3-phenyl-1-((4-((2,2,2- trifluoroacetamido)methyl)phenyl) sulfonamido)propan-2- yl)amino)propyl)pyrrolidin-1-yl)-5- methyl-1-oxoheptan-4-yl)-N,3- dimethylbutanamide (Compound 23);
(S)-2-((S)-2-(dinielhylamino)-3- methylbutanamido)-N-((3R,4S,5S)- 3-methoxy-1-((S)-2-((1R,2R)-1- methoxy-2-methyl-3-oxo-3-(((S)-1- oxo-3-phenyl-1-(((4-((2,2,2- trifluoroacetamido)methyl)phenyl) methyl)sulfonamido)propan-2- yl)amino)propyl)pyrrolidin-1-yl)-5- methyl-1-oxoheptan-4-yl)-N,3- dimethylbutanamide (Compound 27); and
(S)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N-((3R,4S,5S)- 3-methoxy-1-((S)-2-((1R,2R)-1- methoxy-2-methyl-3-oxo-3-((S)-1- oxo-3-phenyl-1-(4-(1-(2,2,2- trifluoroacetamido)cyclo- propyl)phenylsulfonamido)propan-2- ylamino)propyl)pyrrolidin-1-yl)-5- methyl-1-oxoheptan-4-yl)-N,3- dimethylbutanamide (Compound 31).Cited by (0)
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